The UMMS Center for Translational Research on Human Immunology and Biodefense (CTRHIB) is a broad-based interdepartmental program to address, as its overall scientific theme, the role of T lymphocytes n the immunopathogenesis of and protection from category A-C viral pathogens in humans. The CTRHIB is a collaborative effort of senior and junior investigators with expertise in human immunology and research on biodefense pathogens, including translation to clinical studies. The UMMS CTRHIB includes 4 Research Projects, a Technology Development Project (TOP), and 5 Cores: Project 1 will analyze human CD4 and CDS T-cell responses to influenza virus vaccine and natural infection and define the characteristics associated with optimal vaccine-induced immune responses. Project 2 will analyze the interactions between innate and adaptive immune responses to virus infection and their effects on endothelial cell function, with a focus on the plasma leakage associated with viral hemorrhagic fevers caused by flaviviruses and hantaviruses. Project 3 will analyze heterologous immunity in flavivirus infections, defining the effects of amino acid variations on cross-reactive T-cell responses in sequential flavivirus infections. Project 4 will analyze the mechanisms underlying the selection of immunodominant epitopes from large DMA viruses, including poxviruses and herpesviruses (HHV-6). The Technology Development Project (TOP) will develop novel methods and tools for epitope discovery, characterization of virus-specific T cells, and high-throughput expansion and detection of virus-specific T cells to facilitate broad application of assays of cellular immunity. Core facilities will provide program administration/educational outreach, pilot projects funding, and centralized services for clinical studies (subject recruitment and characterization), flow cytometry, and production of MHC proteins for use by the research projects and TOP. The CTRHIB addresses important NIAID research priorities related to biodefense pathogens as well as career development for junior investigators. Organizing these activities in a single research Center facilitates cross-departmental and cross-disciplinary interactions, which will be assessed by periodic independent review.

Public Health Relevance

The UMMS Center for Translational Research in Human Immunology and Biodefense will address key NIAID research priorities through research on human T-cell responses to category A-C viruses (influenza, flaviviruses, hantaviruses, poxviruses, and herpesviruses) and development of new tools for analysis of human virus-specific T cells. The Center provides centralized services and coordination for the research. PROJECT 1: Human CD8+ and CD4+ T Cells Responses to Influenza Infection and Vaccination (TERAJIMA, M) PROJECT 1 DESCRIPTION (provided by applicant): The overall goal of this project is to define the human T-cell responses to influenza infection and to trivalent inactivated influenza vaccines (TIV) in younger and older adults. We hypothesize that (1) human T-cell responses in younger adults will be greater than those in older adults to vaccination and to infection, (2) human CD4+ and CD8+ T-cell responses will be lower to vaccine than to infection and (3) the TlV-induced T-cell responses will correlate with the amount of internal proteins in the individual licensed vaccines. Influenza A virus hemagglutinin (HA) is a target of protective neutralizing antibodies, which are subtypespecific and vulnerable to antigenic drift. CD4+ and CD8+ T-cell responses are thought to be more subtype cross-reactive. It is clear from studies in mouse models of influenza A virus infections that T cells can provide a second important line of defense, especially in the face of marked antigenic drift or shift due to emergence of viruses with changes in HA antibody combining sites, and there are also limited clinical studies which suggest the importance of T cells for protection, especially in a high-risk elderly population. There is, however, only a limited amount of data available on human T-cell responses to influenza infection or vaccination. Importantly there appears to be more subtype cross-reactivity among influenza A virus T cell epitopes than to the antibody epitopes on HA. At present limited data suggest that current TIVs induce low to moderate CD4+ and CD8+ T-cell responses. However, we found some individuals with high T-cell responses to TIV. Recently, we and the other group also found the amount of influenza internal proteins in the TIVs differs. Despite the recommendation and use of about 100 million vaccine doses per year in the US alone, very little is known about TIVs induction of T-cell responses and nothing is known about their contribution to vaccine associated protection.
In Aim 1 we propose to analyze CD4+ and CD8+ T-cell responses to TIV vaccination in younger and older adults. In these studies, we will also compare the three US-licensed TIVs for their ability to stimulate CD4+ and CD8+ T-cell responses and for protection (in older adults).
In Aim 2 we propose to characterize CD4+ and CD8+ T-cell responses to natural influenza infections in younger and older adults and compare them to the CD4+ and CD8+ T-cell responses induced by TIV. These analyses may lead to approaches towards improved influenza vaccines, which can protect against new and emerging influenza virus infections including H5N1 and other non-human strains.

Public Health Relevance

For efficient protection against influenza A virus infection, influenza vaccines need to induce cellular immune responses as well as neutralizing antibody responses, especially in older adults. Despite the recommendation and use of about 100 million vaccine doses per year in the US alone, very little is known about cellular immune responses induced by the vaccines and nothing is known about their contribution to protection, which we propose to study in younger and older adults to help design better influenza vaccines.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-KS-I (J4))
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Quill, Helen R
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University of Massachusetts Medical School Worcester
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Mathew, Anuja (2017) Humanized mouse models to study human cell-mediated and humoral responses to dengue virus. Curr Opin Virol 25:76-80
Ramirez, Alejandro; Co, Mary; Mathew, Anuja (2016) CpG Improves Influenza Vaccine Efficacy in Young Adult but Not Aged Mice. PLoS One 11:e0150425
Townsley, E; O'Connor, G; Cosgrove, C et al. (2016) Interaction of a dengue virus NS1-derived peptide with the inhibitory receptor KIR3DL1 on natural killer cells. Clin Exp Immunol 183:419-30
Woda, Marcia; Friberg, Heather; Currier, Jeffrey R et al. (2016) Dynamics of Dengue Virus (DENV)-Specific B Cells in the Response to DENV Serotype 1 Infections, Using Flow Cytometry With Labeled Virions. J Infect Dis 214:1001-9
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Woda, Marcia; Mathew, Anuja (2015) Fluorescently labeled dengue viruses as probes to identify antigen-specific memory B cells by multiparametric flow cytometry. J Immunol Methods 416:167-77
Becerra-Artiles, Aniuska; Dominguez-Amorocho, Omar; Stern, Lawrence J et al. (2015) A Simple Proteomics-Based Approach to Identification of Immunodominant Antigens from a Complex Pathogen: Application to the CD4 T Cell Response against Human Herpesvirus 6B. PLoS One 10:e0142871
Jaiswal, Smita; Smith, Kenneth; Ramirez, Alejandro et al. (2015) Dengue virus infection induces broadly cross-reactive human IgM antibodies that recognize intact virions in humanized BLT-NSG mice. Exp Biol Med (Maywood) 240:67-78
Mathew, Anuja; Townsley, Elizabeth; Ennis, Francis A (2014) Elucidating the role of T cells in protection against and pathogenesis of dengue virus infections. Future Microbiol 9:411-25
Outinen, T K; Mäkelä, S; Huttunen, R et al. (2014) Urine soluble urokinase-type plasminogen activator receptor levels correlate with proteinuria in Puumala hantavirus infection. J Intern Med 276:387-95

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